Analysis of the nature and sequence of cell-derived and environmental signals for progressive development of the fully activated macrophage was the long-term goal of our original proposal. Significant progress has been made towards the elucidation of this differentiative pathway. this progress is largely attributable to the recent availability of highly purified and cloned cytokines which were used in conjunction with macrophages derived from the endotoxim "hyporesponsive" C3H/HeJ mouse strain. In the studies described herein, we will continue to utilize this extremely sensitive system to extend our original findings. We propose to analyze the control mechanisms which govern colony stimulating factor (CSF)- and gamma interferon (IFN-y)-induced effects on macrophage proliferation and differentiation. We will also assess the role of these cytokines in the activation of macrophages to kill Salmonella typhimurium intracellularly or to produce inflammatory mediators, such as elastase or collagenase. In addition, we plan to utilize bone marrow-derived macrophages from endotoxim "responder" and "nonresponder" mice to delineate the role of cytokines in the acquisition or endotoxin sensitivity. Lastly, we propose to define the contribution of ancillary, serum-derived signals in cytokine-induced differentiation by using a "defined, complete" serum-free medium. The characterization of the cytokines involved, as well as delineation of the specific sequences of intra- and intercellular signals that result in the development of the fully activated macrophage, could provide novel therapeutic approaches for diseases in which activated macrophages have beneficial or detrimental roles. The ability to stimulate activation of host macrophages might benefit patients who have neoplasms or infections with intracellular pathogens. In contrast, the capacity to control macrophage activation such that the production of toxic mediators is mitigated may be beneficial to patients who suffer from chronic inflammatory diseases such as rheumatoid arthritis or periodontal disease. Finally, an improved understanding of the relationships between the state of macrophage activation and endotoxin sensitivity might provide insights for successful treatment of septic shock or other complications of Gram negative bacillary infections.